The endogenous neurotransmitter acetylcholine (Ach) mediates diverse physiological functions in the peripheral and central nervous systems (CNS) via muscarinic and nicotinic subclasses of acetylcholine receptors (AChRs). The nicotinic acetylcholine receptors (nAChRs) are ligand-gated cell surface ion channels that are selectively activated by the natural product nicotine. The diverse molecular subtypes or variants of nicotinic acetylcholine receptor are based on the pentameric structure of the receptor. The nAChR subtypes are formed from diverse pentameric combinations of nine molecularly distinct alpha subunits and four molecularly distinct beta subunits. A particularly interesting molecular target for therapeutic intervention is the alpha-7 nicotinic receptor subtype, which is comprised of five alpha-7 monomeric subunits. Thus, agonists which are selective for the alpha-7 receptor have potential to treat a range of diseases. Alpha-7 agonists are expected to be especially useful for the treatment of CNS disorders associated with cognitive deficits. This expectation is based on beneficial effects of alpha-7 receptor activation on cognition, learning and memory. At the same time, selective alpha-7 agonists are expected to cause fewer or less severe undesirable side effects, e.g. nausea, vomiting, tachycardia, which are mediated by the activation of certain other nicotinic receptor subtypes as for example by the non-selective agonist nicotine.
As such, there is a need for additional selective alpha-7 agonists for the treatment of CNS disorders associated with cognitive deficits.